“We now have biological evidence that the triggers for ME/CFS may involve distinct pathways to disease, or, in some cases, predispose individuals to the later development of serious comorbidities.” Dr. Mady Hornig.

The Subset Makers

Over the past couple of years the Simmaron Research Foundation and Center for Infection and Immunity at Columbia University and others have begun to pump out some long awaited subsets. This week, new findings were published by Columbia and Simmaron that define 2 subsets.

They’re not the usual suspects (infectious trigger vs non-infectious trigger; gradual onset vs acute onset). In fact, they involve subsets few would have predicted a couple of years ago. They suggest that we might be in for some real surprises over time.

Short Duration vs Long Duration Subset: Two years ago, the Simmaron Research Foundation collaborated with Ian Lipkin and other doctors to uncover a subset few had anticipated: short duration patients vs long duration patients.

The Atypical Patient or “Peterson Subset”: Now comes a subset of atypical chronic fatigue syndrome (ME/CFS) patients (the “Peterson Subset”) that Dr. Peterson had long wondered about. These patients had ME/CFS but tended to follow a different course. Some had had unusual exposures (unusual infections, blood transfusions); others developed serious illnesses (cancer, autoimmune diseases, etc.) that Dr. Peterson didn’t see in the rest of the population.

Dr. Hornig talked about how the atypical subset came about. Like so many breakthroughs in medicine it took a careful and observant doctor/researcher to bring it about. This study, she said, was a testament to:

“Dr. Peterson’s clinical acumen, his long-term follow up of this patient population and his attentiveness to the full range of complex, serious medical disorders that might develop. The classical group had been followed for similar lengths of time but had not developed these more severe, serious comorbidities.”

The atypical vs classical distinction was pre-established by Dr. Peterson before the analysis. Based on his wide-ranging clinical experience, the atypical group stood out for either: 1) the presence of unusual precursors (triggers) of ME/CFS or; 2) the development of more unusual and severe comorbidities over varying (and often long-term) intervals after ME/CFS onset.”

The atypical group turned out to be quite different

Dr. Peterson felt the unusual outcomes weren’t just the result of chance: something different was going on – something that he felt as a doctor needed to be identified. What if, he thought, there was a way to identify these unusual patients before they started developing these significant illnesses. Then he could do more extensive cancer or immune screens and watch these patients more closely.

Plus, these patients could be inadvertently bollixing up the results of ME/CFS studies. Peterson was so sure, in fact, this subset was different that he had its effects assessed during the first Simmaron/CII spinal fluid study. Peterson turned out to be right: the atypical subset had such an effect on the results that it had to be removed.

The next step was a study comparing the two groups. Using Dr. Peterson’s spinal fluid samples, The Center for Infection and Immunity (CII) at Columbia found that “Peterson Subset” not only had markedly different immune findings but displayed a different pattern of immune results as well. Dr. Peterson is Scientific Advisor to Simmaron and Gunnar Gottschalk was its Research Manager.

The Atypical Subset

What does a typical chronic fatigue syndrome (ME/CFS) patient look like? Something like someone who suddenly comes down with a flu-like illness and never recovers. They may get better or they may get worse, but they don’t come down with cancer, an autoimmune illness, seizures or other significant illnesses.

An atypical patient, on the other hand, might have a history of viral infection (viral encephalitis) or have been exposed to unusual pathogens during foreign travel or had a blood transfusion before becoming ill. They also tended to be more severely cognitively impaired and had more neurological complaints. They tended to suffer from severe diseases as well.

Many of these illnesses appeared long after the ME/CFS diagnosis. In fact, at the time of diagnosis these patients looked like a typical ME/CFS patient. This study suggests, though, that very early on, something different was happening in their central nervous systems.

Immune “Exhaustion”?

This “broadly based” immune study compared 51 cytokines and other immune factors in the cerebral spinal fluid of 32 typical and 19 atypical ME/CFS patients. These numbers at first glance may seem small but they’re actually quite large for spinal fluid studies.

The Simmaron Research Foundation/Center for Infection and Immunity’s prior studies suggested that typical ME/CFS patients’ immune systems went on high alert for the first couple of years of illness but then went into slumber mode. In fact, it was more than slumber mode: their immune activity essentially tanked – leading to the hypothesis that frantic activity of the first couple of years might have left their immune systems depleted.

Autoimmune diseases were amongst the unusual comorbidities found in the atypical subset.

This study suggests that the “Peterson Subset” follows a markedly different pattern. The major burst of immune activity early on followed by equally dramatic downturns found in the typical patients is gone. Instead the study suggests that the immune systems of the atypical patients essentially started off low and stayed low.

As the illness proceeded, though, the pattern changed again: the atypical groups’ immune system actually revved up again.

When I asked if immune exhaustion was bringing the immune system down early in the atypical group, Mady Hornig replied:

“We don’t know yet. Our additional finding of an interaction of diagnostic subset with duration of illness – wherein the atypical group showed a pattern of increased levels of immune molecules with longer duration of illness, as opposed to the dampened immune profiles in the classical group with longer illness duration compared to classical ME/CFS in the early stages of disease (as we had seen in the immune profiling work based on plasma samples) – suggests that the response tends to be more suppressed at the onset of ME/CFS in the atypical group.”

Could that dampened immune response early in their illness be contributing to the illnesses the atypical group experienced later? Dr. Hornig again cautioned about the need to replicate the study but suggested it might. A viral trigger could have blasted their immune systems or vice versa – a problematic immune system could have allowed a virus in …

“However, dampening of inflammatory (so-called Th1/Th17-type) responses might be expected to restrict an individual’s ability to keep problematic microbes from replicating. Certain viruses – even common ones implicated in ME/CFS in some studies, such as Epstein-Barr Virus (EBV) – are well-known to be associated with development of certain cancers; however, only a fraction of those infected with EBV develop cancers.

It is a bit of a chicken-egg conundrum: EBV could alter immune responses of T/NK cells to increase cancer risk, or altered T/NK responses at the time of EBV infection could be the critical factor. Alternatively, reduced Th1/Th17-type immune profiles after infection – along with reduced T regulatory cell responses – might skew some individuals toward autoimmunity, raising the risk for more severe autoimmune diseases, including atypical multiple sclerosis or even autoimmune-mediated epileptiform disorders. But at this early juncture this remains only speculation.”

Epstein-Barr Virus (EBV) brings up the age and exposure question. It’s much more difficult for the immune system to corral or ward off EBV if EBV is encountered for the first time at a later age (during or after adolescence). That difficulty shows up as the months long fight to beat EBV called infectious mononucleosis.

A meta-analysis of studies examining many environmental risk factors for multiple sclerosis (including vaccinations, comorbid diseases, surgeries, traumatic events and accidents, exposure to environmental agents, and biochemical, infectious, and musculoskeletal biomarkers) found that only three were associated with an increased risk of coming down with MS. Two of those concerned EBV (having had infectious mononucleosis, IgG seropositivity to EBNA). (The last significant factor was smoking).

Could a later exposure to EBV which resulted in infectious mononucleosis be the straw, so to speak, that ultimately broke the camel’s back for some of the atypical patients?

Dr. Hornig agreed that a study parsing out the rates of infectious mononucleosis in ME/CFS could be helpful but said it was hard to know at this point if IM played a role. She said that the CII group was investigating EBV further:

“Hard to know (if late exposure to EBV is involved)- we are looking for clues suggesting greater risk for autoantibody-mediated disease in EBV and other virally-exposed subsets of ME/CFS. We do know that females have higher risk for autoimmune disease, but the sex skew only begins after puberty (when females might have come down with IM [Infectious Mononucleosis]).”

Poor Networking

Not only was less immune activation present earlier in the atypical groups but a network analysis indicated a weaker immune network was present as well. These network analyses assess the “wiring” present in the complex immune system.

Immune mediators called cytokines (and other immune factors) form these networks when they communicate with each other to drive an effective immune response. While a central immune network was found in the typical patients, no such network connection was found in the atypical group. That suggested a less robust immune response was occurring.

Pro-inflammatory Markers Down

A less than robust immune response to an infection could play a role in the atypical group.

Surprisingly, the atypical group’s spinal fluid had lower levels of two pro-inflammatory cytokines, IL17A and CXCL9. Given the atypical group’s increased neurological and cognitive problems one would have expected the opposite.

That suggested that the atypical patients might be more than different in degree; they might be different in kind. The TH17 pathway that underlies many autoimmune and inflammatory diseases, and which the authors believes may be contributing to the typical ME/CFS group, doesn’t appear to be in play in the atypical group. In fact, the authors suggested the researchers vigorously pursue “alternate, nonimmune mechanisms of pathogenesis in more complex, atypical patients with ME/CFS.”

Dr. Hornig suggested genetics might play a role or that a different kind of immune response; one that was a bit too weak early on to knock off a pathogen, was another possibility.

“I think it may rather be the kind of immune response (inadequate inflammatory responses that might serve to contain an infectious agent upon first exposure, with skew towards autoimmunity or permissiveness to later uncontrolled growth of abnormal cells – i.e., neoplasia) and its timing (too little early on, with some limited immune escape at later time points, allowing for some inappropriate inflammatory type responses after the infectious agent has already had an opportunity to set destructive processes in motion – but too little and too late to contain or eradicate the pathogen).”

That could set up what Dr. Hornig called a “smoldering inflammatory process”.

Cause(s)

What might be causing the immune systems of the atypical group to act so differently early on? Dr. Hornig warned that it was essential that the study results be confirmed by a larger study but suggested that different triggers (unusual infections) or genetic vulnerabilities (environmental susceptibility, immune response, autoimmunity genes) or even one’s age at exposure could play a role.

Results Suggest Atypical ME/CFS Patients Should Be Screened for Cancer and other Diseases

As with any single study the results need to be validated in studies by other labs using other patients to be validated. If they are, though, they could help doctors and patients. Dr. Peterson said:

“Early identification of patients who meet the usual clinical criteria when first diagnosed but then go on to develop atypical features would help clinicians like myself identify and treat these complex cases and even prevent fatal outcomes.”

Hornig and Lipkin suggested that atypical ME/CFS patients should be screened for cancer just as patients with paraneoplastic syndromes are. Paraneoplastic syndrome occurs when an immune response against cancer affects other parts of the body, often before a diagnosis of cancer is made.

How Common are Atypical Patients?

How many patients are “atypical”? In her answer to that question Mady Hornig called for more comprehensive studies to fully understand ME/CFS.

“Though we know comorbidity rates in ME/CFS are thought to be high for quite a number of conditions (allergies, gastrointestinal problems), few studies have addressed this issue in a systematic manner.

It is rare to find physicians who specialize in this disorder, let alone follow the same individuals over time. Given the finding that prior to the development of these other serious comorbidities, all members of this subset met research diagnostic criteria for ME/CFS and would only later qualify as “atypical” based on subsequently developing comorbidities (over many years), we desperately need longitudinal studies that monitor for such issues.

The bottom line is that we don’t know what percentage of ME/CFS patients are “atypical”.”

It’s not clear what percentage of ME/CFS patients are atypical but they may have already had a dramatic impact on ME/CFS research and treatment. Dr’s Fluge and Mella started the Rituximab saga in ME/CFS after noticing improvements in the fatigue, etc. of ME/CFS patients who’d come down with cancer; i.e. atypical patients.

Dr. Hornig has called the spinal fluid samples Dr. Peterson has collected over the years a “precious” resource, and she highlighted his persistence in collecting them over the years.

“There also may be long-term cohorts at some ME/CFS clinical sites that might be available for closer examination, at least with respect to clinical patterns and disease/comorbidity trajectories. But most of these sites are unlikely to have cerebrospinal fluid samples (let alone plasma samples) banked in a repository for years!

The suggestion that biological pathways in the CNS already look different even before the onset of these comorbidities implies not only that screening and surveillance are likely to be important to ensure better long term care for individuals with ME/CFS, but also that treatment might need to be tailored differently in classical vs. atypical subsets.”

Similar Issues Showing Up in Other Neurological Diseases

Subsets are common in neurological diseases.

Gunnar Gottschalk, a co-author of the study and medical student is a former research manager for Simmaron Research Foundation. He’s been deeply immersed in ME/CFS research for several years and continues as a Trustee of the Foundation. Gunnar noted that the neuroscience lab he is working in is studying similar issues in Parkinson’s, Alzheimer’s and other neurodegenerative diseases. It’s not that the same findings are present but that highly abnormal spinal fluid cytokine findings are showing up in all these diseases – including ME/CFS.

Nor is this study’s general finding – that atypical patients can be differentiated from typical patients in ME/CFS – unusual in the neuroscience field. Virtually every neurological disease, Gunnar said, appears to be studded with subsets. Different types of multiple sclerosis, for instance, have been identified using similar kinds of spinal fluid analyses.

Noting that developing animal models are critical to understand what’s happening in the brain, Gunnar said he wouldn’t be surprised at all if some animal models which have been developed at great cost for other diseases wouldn’t eventually be helpful in some ways for ME/CFS.

Next Steps

This is not it for the spinal fluid and the atypical patients. Metabolomics and proteomics studies are next in Phase 2 of the study, which is being funded by Simmaron. Gunnar noted that the cytokine studies can identify important pathways, but the metabolomics studies can provide more detailed results and he’s eager to see how they turn out.

Dr. Hornig has a long, long list of studies she’d love to do in ME/CFS. This is a disease, she feels, that is calling out for comprehensive studies. She wants to analyze blood, fecal and spinal fluid samples collected at the same time to assess what infection or environmental insult the patient is reacting to.

Comparing immune profiles in the blood and spinal fluid could, for instance, help tell her whether powerful immune cells are squeezing though the blood-brain barrier and wreaking havoc in the brain. Determining that immune cells from the periphery are in the brain would open an entirely new window on ME/CFS.

The gut is another area primed for research. Dr. Hornig pointed out that it’s clear that the bacterial communities in our gut shape our immune response. The TH17 profile found in some patients that tilts the immune system towards inflammation could derive from danger signals produced in the gut. Similarly the TH2 profile found in other patients that tilts them towards autoimmunity could come from the gut as well.

What Dr. Hornig wants is “system-biology” work that ties all these systems into a coherent whole. A gut level disturbance could, for instance, end up impacting virtually every system involved in ME/CFS – including the central nervous system.

“Further systems biology-type work will help us delineate how altered gut microbiota might translate into faulty signals – ranging from bacterial or human metabolites, including a range of immunity-modifying and neuroactive molecules, to immune molecules, to autonomic/vagal nerve axis effects – that then access the CNS (perhaps involving damage to the integrity of the blood-brain barrier to allow entrance of these aberrant signaling molecules) and disrupt brain function.”

In fact, Mady Hornig and Ian Lipkin do have most of the samples they need to begin this work. In what must have been one of the stranger NIH grant awards ever, however, the NIH funded the collection of an enormous amount of samples taken at four points over a year in 250 ME/CFS and healthy controls, but has not funded the analysis of these very same samples.

“In the more recent longitudinal NIH study we have no funding at all for laboratory studies, but have a unique banked set of well-characterized samples (oral, fecal and blood).” (bold added)

Having so many samples just sitting there is astonishing, and hopefully the second half of the study will get funded.

When I asked Dr. Hornig about funding the metabolomics and proteomics work she said that the metabolomics and proteomics assays had been run – but only for a subset of patients. The CII, she said had funding:

“Only for analysis of a subset of the Chronic Fatigue Initiative main study cohort samples (and this assay work is completed with analysis in progress) – not for the latest 125+ cases and 125+ controls based on the 1-year, NIH-funded study with 4 serial sample collections.

We don’t have any funding to follow up on candidates identified, including validation, quantitation and correlation with genetic, epigenetic and RNA-based assays.”

A Foundational Approach To ME/CFS Proposed

Large foundational studies are needed to take ME/CFS to the next level

Dr. Hornig went further, though, and called for a “foundational” approach to chronic fatigue syndrome (ME/CFS) that included national registries which would be able to tease out subsets and determine just what happens as people get ME/CFS.

“To support this sort of work on a larger scale, fundamental and foundational work is required. National registries of ME/CFS populations could be developed that would have the capacity to identify the range of preceding potential triggers to disease, to define comorbidities at the time of diagnosis, as well as to longitudinally track the new occurrence of comorbidities in ME/CFS populations over time.”

That is the kind of vision this field needs. That is the kind of vision that should be able to excite NIH and other funders.

The Simmaron Research Foundation’s unique spinal fluid work with the CII has thus far helped to identify two potential subsets in ME/CFS. Validating the atypical or “Peterson Subset” could lead to a new understanding of how ME/CFS works and open new treatment options for patients. The SRF looks forward to further collaborations with the Center for Infection and Immunity and Mady Hornig and Ian Lipkin as it works to redefine ME/CFS biologically.

Poll Note: The poll will only allow one option to be picked. One positive response suggests you may be an atypical patient. Keep in mind, though, that this is early research on subsets and further studies are needed to verify the findings.

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Do You Have Typical Or Atypical ME/CFS?

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Please select an option!

My ME/CFS onset occurred during foreign travel

My ME/CFS onset began with an unusual infection (eg West Nile Virus)

My ME/CFS onset occurred after having had a blood transfusion

Since getting ME/CFS I have been diagnosed with an autoimmune disorder

Since getting ME/CFS I have been diagnosed with an inflammatory disorder

SInce getting ME/CFS I have had seizures

Since getting ME/CFS I have been diagnosed with cancer

Since getting ME/CFS I have not been diagnosed with any of the above disorders

77 Comments

Neena

Dx’d w/fibromyalgia and chronic fatigue syndrome 29 years ago by Don Goldenberg, MD, Newton-Wellesly Hospital, Massachusetts, when symptoms emerged following a bc mastectomy w/a silicone implant reconstruction. Manufacturer(s) did not inform doctors that silcone implants were contra-indicated for persons w/auto-immune disorders nor that the outer covering was permeable. Past few years major increase in overwhelming fatigue and muscle weakness…
no treatment available. Now children and men are being dx’d…5 million…where is all the research, research, research…millions of us need help.

Aidan

17+ Million People Worldwide have this illness but a lot more than that are actually diagnosed as something else when they have this illness instead plus EDS is highly tied to the illness as well so that brings the count much much higher some have even said that CFS has actually

surpassed HIV/AIDS that there are more Sick with this & no proper World count has ever been done & not to forget one’s told they have a Lyme diagnosis but have CFS/EDS instead…It takes some decades to be properly diagnosed & not everyone is on internet social

sites either or see any Doctors in this field ever…Lot more suffering across the Globe than we really can Fathom…

Aidan

There work is only small & unless it is fully Replicated & fully Published it will not be accepted I doubt very much that theory will be proven as any Cause besides back in 400 B.C. when EDS

was first mentioned there were no Nuclear facilities during that time nor Nuclear Weapons either & it is now turning out that so called CFS
is Ehlers-Danlos Syndrome all along undiagnosed the term CFS should

be taken out entirely it alone stalls Research & is not taken seriously…95% of Patients diagnosed with CFS have EDS the other 5% have other connective tissue disorders a quote by Dr. Rodney Grahame

Hypermobility Unit in London UK the top Ehlers-Danlos Syndrome Researcher on the Planet he knows immediately in Office how to diagnose EDS types, most Doctors have not a clue & that is a fact about

getting the proper EDS diagnosis…Some take decades to be properly diagnosed…I doubt the theory of Radiation will pan out however Dr. David Bell now treats Radiation sickness close to Buffalo NY but he

also is on the wrong track just theories unproven ones…

Issie

I have EDS, and had Eherlichia and Protomyzoa Rehumatica. So much more………

What is this idea about radiation? I’ve not heard of this hypothesis? Back in the late 50s when radiation first started being used – my parents generation thought it was a healthful thing. They would go get radiation treatments. Yes lay there and be radiated! Not too long later my mom’s first child was born – stillborn and with spina bifida. Then along came me and my sis. Could her and my dad’s radiation caused an epigenetic change and therefore affected their offspring? I’ve not researched this. Just asking if anyone knows.

Issie

Helene Tomlinson

I have ME/CFS, chronic lyme, hashimoto’s, celiac disease, leaky gut syndrome. In 2009 I came down with a severe flu like illness. I have never been the same. In the few months preceding that illness I developed cystic acne all over my face, severe exhaustion, etc. I had not had acne in my previous 49 years of life.

Currently receiving antibiotic treatment for chronic Lyme on pill form.
I kept working as an RN after the illness started until I hit a wall in 2013, landing on bedrest for 22 months. I became disabled at that time and remain so. I developed chronic fatigue, memory issues, mood issues, black outs, neuropathy, severe pain, narcolepsy, celiac disease, hashimoto’s, etc. The list goes on and on. I’ve contemplated suicide several times.

Nutrition and supplements have allowed me to regain some function. Occasionally I can drive, go on short trips to the grocery store, etc.

Please continue working on this disease. We need you desperately. There are so many of us out here with no voice. We don’t have the energy to make our voice heard!

Cort Johnson

So interesting Helene – I wonder what that acne meant? Glad you have regained some functioning…Hopefully Simmaron and Columbia and the other organizations working on this disease will get the funding they need…The good news is that we’re getting really good people – now we need more money.

Julie Engle

Cystic Acne (as Helene and “Y” both reported with CFS), rashes, and many other new dermatological symptoms (such as “stretch marks” on adult men and non-pregnant women) may likely be due to Bartonella species. If/when more research money becomes available, I hope Simarron and others will do more pathology studies with Dr. Peterson’s samples, specifically looking for Lyme Disease and other tick-borne co-infections, especially parasites. The various CFS subsets may be due to the specific combination of microbes the patients harbor. (See Dr. Alan MacDonald’s recent studies showing parasites, ie, nematode worms, and spirochetes in MS, Alzheimer’s and Lyme patient’s brains and spinal fluid.)

Cort Johnson

Yes millions of dollars have been spent on this illness but that’s a pittance compared to most diseases. The human body is a tough nut to crack! Many more dollars have been spent on diseases like multiple sclerosis over time and while there are drugs there is as yet no cure.

I would hope for something that helps but does not cure first. That would be a good start…

Justin Reilly

There will be a cure at some point, if that will be in our lifetimes, who knows. But a huge amount of progress can be made if the appropriate amount of money went into this disease and that money stopped going into fake research such as that done by the PACE authors and CDC.

K

Actually the amount of funding for cfs/me research coming from the nih is grossly, ridiculously, outrageously low, $5 mil per year. There is no other disease that destroys the patients quality of life so badly AND is so poorly funded than cfs/me. I hate the government and the medical community for not caring about us.

Cort Johnson

Carollynn

Cort, might you include Hawaii in your “foreign travel” group? I got sick right after traveling there, and Dr. Chia reports that many of his patients (predominantly from S. Cal.) get sick after traveling to Hawaii or Mexico, and he notes that others have traveled abroad, that us humans just don’t have the same antibodies to things that people do who grow up some place. Also, it’s public sanitation systems. Mt beloved Hawaii and Mexico still allow cesspools that leak into local water systems and into the ocean http://health.hawaii.gov/wastewater/cesspools/–90,000 still in that state! In places where people swim or fish, water quality is assessed only by the presence of bacteria, not of viruses. So I may have become infected by swimming, or by sushi. Chia gave me a paper in which it was suggested that screening fish for viruses would be an important adjunct in assessing if water is safe to swim or fish in. I can’t find it but will keep looking and post it later; hoping you can add Hawaii to your list. Meanwhile, you can do a PubMed search on “enterovirus sewage Hawaii” and find many related articles.

Carollynn

The corrected link to the Hawaii Dept. of Health above gives numbers of cesspools on each island.

For me, another important piece of info in all this is about the fish we eat: no countries test fish for viruses, so any fish could make someone sick, someone who never traveled to the waters it was fished from. After I became sick, my preference shifted on its own from eating raw fish to only cooked. Cooking fish adequately will kill viruses. None of this undercooked salmon or scallops, now popular with chefs, for me!

Lori

Carollynn, may I ask how your illness started–symptom wise? I too was on vacation–not to a foreign country–but at a cottage 800 miles from home. Dr figured I had a virus, but I still think it was the water. It was a great vacation — little did I know it would change my life forever!

Cort Johnson

Allie sent this over in an email. She had trouble posting it on the site. (I believe that HSCT refers to hematopoietic stem cell transplantation)

I was Dx with chronic EBV after a near fatal bout of autoimmune EBV hepatitis when I was in my teens. Struggled with ME/CFS for 30 some odd years. In 2012 Dx with MS with active brain lesions.

After the MS meds failed me and still having active brain lesions I had HSCT. A reboot of the faulty immune Sx with chemo followed by my own stem cells to regrow a new immune Sx that defaults to tolerance.

Praise the Good Lord I got my life back. My prayer is this procedure will be available to all who need it. I’m truly blessed.

'matthew Jones

My CFS started a few months after having Lyme disease (diagnosed by a professor of infectious diseases). i live in the UK but caught the lyme disease while Hiking in America. Does that make me typical or ayptical?

Carollynn

That’s an interesting question, Matthew. Per Dr. Chia’s suggestion that people get sick after traveling to places for which the locals (but not visitors) have anti-bodies, that may be only true for viruses and bacteria. Lyme would be one thing that both locals and visitors would be susceptible to. Sorry that your visit to the US sent you home with this unwanted companion.

Issie

Having had protozoa issues myself and putting much effort into “taming” them and doing tons of research – what it does tell you is your immune system wasn’t strong enough to keep things under control or to properly eliminate the protozoa. My primary doc, feels that those who have such strong issues with the and hronic Lyme or other types protozoa – the immune system isn’t properly detecting. We may have to Co- exist and just “tame” them down. Finding the right way to do this for the most benefit is challenging. I’m happy to say, my doc feels – I may have done this for myself. I no longer herx with any type treatments now.

Issie

Issie

Something that may be of interest, when I had my blood draw for the Lights study, they asked if I would agree to have my samples stored for later and if I would agree to have my data included into a combined database of other researchers who are working for us to help find answers. My data, markers, findings can be used with other potential research projects. Of course, I agreed. Especially if it may help others and if I may get more puzzle pieces to help my picture to come more clear.

Issie

Dawn

What about Aplastic Anemia? I have it and it is a bone marrow failure disorder. Mine is a genetic defect I the chromosome of bone marrow production. The outer protective cover of the gene is not long enough. I went through a 2 year clinical trial at NIH. I know I have ME/Chronic Fatigue Syndrome but have been unable to find a willing physcian to offically diagnosed and give me some sort of relief or treatment. I am beyond frustrated and exhausted and want my life back!

Carollynn

Dawn, I’m so sorry for your health, frustration, and anguish. I wish I could offer you more than perhaps an interesting connection with other symptoms. So much of what we have with ME/CFS needs so much more study–and then so many more capable, compassionate physicians. So forgive me if this is merely “interesting,” but low blood volume is common among ME/CFS patients, and bone marrow is where red blood cells and most of our white blood cells are made. I can see how a bone marrow disease would be connected to MC/CFS. Maybe your history will connect the dots for a researcher about these issues and others. I hope that help is on the way for you (and all of us) soon. There may be another spot in the HealthRising forums with recommendations about doctors in your area. Good luck on finding someone at least validating of your experience and caring about your suffering.

Vlynx

Dr. Kaufman at the Open Medicine Clinic in Mountain View, CA is finding high levels of unusual antibodies in a number of his patients. I don’t know the percent or if these patients are in a distinct class, but I gather that he is finding these things at a pretty high rate. They are things I’d not heard of before, such as the GAD-65 autoantibody (associated with higher risk of Type 1 Diabetes but also with neurological syndromes such as Stiff Person Syndrome) which I have.

He is also finding high levels of antibodies to autonomic receptors (muscarinic and beta-adrenergic), which I also have. These are measured by a lab in Germany (CellTrend GmbH) and the test is based on the work in the paper I cite below (note that Fluge & Mella are coauthors). The paper also suggests that these autoantibodies might be indicators of response to rituximab. CellTrend offers the test for diagnostic purposes for CFS and POTS (not clear what one does with this info, yet, however). The test is interesting, though, albeit expensive.

However, it appears to me that elevation of these autoantibodies is not necessarily a special subset such as you discussing, as it was found in about 30% of CFS patients. Note that these autoantibodies are commonly found in healthy controls, it is the elevation in their numbers that makes the CFS patients exceptional.

Cort Johnson

Vlynx

Sorry that was a but muddled. To be clearer, I have GAD65 autoantibodies, not Stiff Person Syndrome! (Although I’m stiff and startle easily, it’s nowhere near the degree of people with this devastating disorder).

weyland

What stands out to me, as a classic patient, was the high level of interferon alpha in the early classic patients. From what I can tell, this finding is highly consistent with viral infection of the CNS and isn’t seen with bacterial infection or other neuroimmune disease (i.e. MS). Did the researchers have any comment on that Cort?

November Girl

I’m glad to see the short duration subset mentioned. I have a first cousin who was very ill for two years, then recovered. I asked her once what she took as treatment. Her answer was anything that someone suggested. She has a very strange immunological profile to begin with; strange for CFS and strange for the general population. It would be helpful is a biomarker for short or long term could be found.

Carollynn

Hi Lori–I think our body often tells us when something effects us, like you “know” about the water, and I knew to not have raw fish or rare meat anymore. It’s also occurred to me that if water sanitation problems are a culprit, cesspools in places that aren’t tropical could leak into wells and water systems to make people sick elsewhere–and again the water is not tested for viruses, just bacteria. To answer your question, the symptoms that sent me to the doctor in 1998 were unbelievable nights sweats and a red itchy, blotchy, weepy rash on my chest and back, swollen lymph nodes in my neck, sore throat, whispery weak voice, exhaustion. My doctor at that time diagnosed me with EBV, though Chia thinks otherwise based on my travel history. I spent two years kind of half-sick with mono (still working; didn’t think I could “afford to be sick”!), got worse, took a one-monht lead of absence and finally got better. Better for three years, and then I got really sick, had to stop working, etc. Too bad I hand’t been diagnosed with CFS even, and of course now we know people can have remissions for a time. I saw Dr. Chia first in 2004 after I was at my worst in the release that continues to this day, and the original lab work from 1998 saying EBV was not available for his review. But even in 2004 my EBV titers were incredibly high, which Chia measured along with a few others pathogens. Higher than EBV was Coxsackie B5, an enterovirus which is his specialty. I also had elevated levels of HHV-6, an echovirus, and Chlamydophila pneumonia (a bacteria that behaves more like a virus). When I have my worst crashes now, I experience similar symptoms to the ones I had in 1998, but of course I’ve developed a lot of other symptoms and comorbidities, notably chronic HHV-3/zoster/shignles. And how about you? What were your symptoms when you got sick?

Lori

Hi Carollynn, thanks for replying. I absolutely agree, one of the things I’ve learned since getting sick is to go with my gut! I am in Canada and unfortunately our testing and resources for ME/CFS suck to put it bluntly. I was tested for EBV and all showed Reactive, but that’s as far as that went! While we were away, a week in I developed severe diarrhea which lasted 3 weeks. Weird part was I felt fine other than the constant trips to the bathroom! Then all the debilitating symptoms started within a week after that. It will be 5 years this year for me. I’m not as bad as I was for the first 2 or 3, which I have a Naturopath to thank for–I had to try something!

Carollynn

I’m sorry you have this, Lori, and how it started. The fear that comes with the perplexing and persisting symptoms early on is hard on top of feeling so unwell, and then having time accrue. If you have any inclination to see a doctor far away, Chia might be a good call. Enterovirus is often more gastro in presentation–but of course I’m not diagnosing you! Short of doctors who can diagnose and treat, you might read recommendations on his Enteroviurs Foundation website http://www.enterovirusfoundation.org/immuneboosters.shtml . There are other pages about pharmaceuticals, too, though there are few. His son was very sick with enterovirus–which is what got him studying this–and was very much helped by Oxymatrine (though I don’t see it listed anymore; not sure why) and works full time now in their lab, co-authors some papers. I take most everything listed here, and though I’m often homebound for a couple of weeks at a time, I can “save up” for a big outing here and there. If it weren’t for these and some other supplements (and acupuncture, and my incredibly supportive husband) I would still be among the bedridden. (Just on this subject, I do better on the product called Immunocal, rather than the Immunovir listed here. The -cal version tastes better too!)

Dianne

My story isn’t covered by the categories. I got ME/CFS after a long-lasting serious viral (probably) infection that lasted five weeks. I assume it was infectious because my roommate had it at the same time. We both recovered over Thanksgiving weekend in 1984, even though we were in different states at the time. She stayed well.

It came back for me in January of 1985, although there had been brief periods of feeling sick before that. The real reason I think I belong in the atypical category is that in 1991 I was diagnosed with disseminated histoplasmosis. I was far from the area where this is contracted so I had to have caught it earlier in my life and the ME/CFS hit my immune system so hard (at least this is how I think of it), that it came out of containment.

Diagnosis took so long (I think I was deteriorating pretty much from the start of the Me/CFS) because once histo is contained it is supposed to stay that way–it is not supposed to come back. I almost died from it. I have always felt that I was sicker than the average person with ME/CFS and this would explain it. I would be dead without my meds.

Jan

My ME began with encephalitis, best as we can work out after the fact (I went to not a real good clinic at the time).

I have not been diagnosed with any other *specific* disorder, but I have “red flag” signs (yes, signs–like blood tests and stuff you can see on examination) and symptoms that could go along with any of several other major diseases. If anything meet enough criteria to be diagnosed with any particular one of them, which it doesn’t.

Eilidh Hewitt

This research is very interesting to me as we have a long history with ME in my family.

1960 I first became ill in 1960 when I was ten, I had what I think was Glandular Fever and never fully recovered to my former health or stamina and had bouts of illness on and of for the next 28 years.

1984 age 12 my second eldest son fell ill after a throat infection (possibly Glandular Fever) and never fully recovered. He developed fluctuating ME that hit him every few weeks.

1987 age 6 my youngest son developed Glandular Fever and never recovered his previous health and went on a downward path.

Winter 1987/1988 Our area was hit in the winter with a raft of viruses many people got ill teachers pupils etc., what was noticeable was that most people were not immobilised but took about 3 months to recover. I was ill with these and so were my husband and daughter aged 11.

After that, I developed severe ME and so did my two sons and my daughter. Our lives came to an abrupt stop and we all became housebound and bed bound.

My husband did not go on to develop ME though I often thought he might as there always seemed to be something not quite right about him from the time of the virus outbreak.

1996 my husband developed a rash which later turned out to be the first signs of a rare Lymphoma which he subsequently died of 2 years ago in 2015.

All three of my children went on to develop other conditions just as they seemed about to start recovering from the severe ME 17 years later; One son developed Coeliac Disease and Keratoconus the other developed MS and Ulcerative Colitis and my daughter Gastroparesis.

We have noticed that people that are felled with the ME at the beginning and are in wheelchairs seem to recover better than the ones that are able to struggle on. And that children with severe ME like my children often develop other conditions just as they seem about to turn the corner.

Our most severe symptoms were the cognitive ones which we are still struggling with to this day

My oldest son is the only one of the family left standing.

Cort Johnson

What a story Eilidh! You guys have had a really rough time; to have both sons get ill so young and stay ill…My gosh. Thank god your husband was able to stay healthy – and that he stuck with you. Sorry to hear that he passed. I hope that you’re doing OK.

I imagine that if your family got into a genetic study- we could learn a lot. (Dr. Bateman is doing one right now in Salt Lake City.) Where were you when that bad virus swept through town?

Issie

I was thinking this about this family also. The study by Bateman is closed to others for now – if I understood correctly. They are going to have another one starting, but is for only patients who are established there. However the study by the Lights, also in Utah – is looking for families like yours.

I agree about the appreciation for the docs and research. Having EDS, a spinal isn’t recommended for us. So to those who can and did provide this with similar issues to mine – very grateful.

Issie

Eilidh Hewitt

Thank you Cort and Issie for your kind thoughts.
I have always been sad that the destruction of my family has been such a wasted opportunity, a chance for some small compensation of something good to come out of it all. Unfortunately we live in Scotland so no chance here of any interest in our history.
I knew that our experiences could hold a lot of useful information: We were a mini epidemic and part of a much bigger one that took place in the 80s. We all had the same type of ME in spite of differing ages and sexes. We all got worse and improved at the same time. We had an enormous amount of symptoms each and very few that differed from each other. I counted about 60 some more unusual like a painful lock jaw, our mouths opened just enough to get a spoon in. Then my husband developing Lymphoma from the same viral outbreak that caused two of us to relapse into severe ME and the other two to develop severe ME, and so on. The viruses we had were Cocksackie plus Glandular Fever, a very potent mix our consultant said.
However I am thrilled that the research in America is going on at such a pace, it’s quite remarkable! And we will be forever grateful to the researchers that are giving so much of their lives in time and effort to help us all.

Carollynn

I want to take a moment here to appreciate Dr. Peterson and all of the patients who have been seeing him at great out-of-pocket and health expense all of these years. I know that they are fortunate people who can figure out how to pay for it (at great sacrifice for many) as well as that to some extent they are not the most severely ill or they’d not be able to travel there at all, and yet they have, undoubtedly with big crashes later. Dr. Peterson’s wisdom at collecting these samples long ago and following the patients–all private research–has helped move the bar forward for us. It’s slow, but it’s still substantial and I appreciate every effort that has contributed to this study and the future ones built on it.

Ben

Interesting analysis but some caution needed when looking at this many subgroups with a relatively small sample to begin with – some of the subgroups contain literally a handful of people. My statistics is a bit rusty but I think a key point, flagged openly in the paper, is: “Each cytokine served as an individual hypothesis in this portion of the analysis, and thus we did not adjust for multiple comparisons.”.

With the small number of subjects and the number of cytokines and sub-group combinations tested, not adjusting for multiple comparisons means that some associations will arise by sheer chance but seem to have a reasonably low P-value. This is not a criticism of the paper itself, just that we should view it as an interesting result requiring further analysis rather than definitive proof of a definitive subgroup. (Again, this is not a criticism of the paper, more that the funding of ME/CFS research is such that it’s hard for researchers to get enough subjects to be able to do properly statistically valid subgroup analysis. I’m glad we have motivated researchers doing this work, I just wish they had more resources and could do bigger studies).

Daniel

I’ve had ME for over 10 years now. It all began with a series of infections (all the “common ME triggers”, including mononucleosis) during a year. That combined with a 16 year old that didn’t listen to his body caused it to completely crash. Over the years I’ve gotten a bit better, but is still largely bedridden. Late 2016 a big lump started growing on my throat, after a bunch of tests they discovered i have Hodgins Lymphoma. Stage 1A, so couldn’t be much better if we look at the positive! They found either traces of or an active EBV infection in my bone marrow tests.

I would be very interested in sending you some of my sample results – But i live in Norway so I imagine that it would be tricky, hehe.

Y

Almost the same history and complaints as Helene Tomlinson.
“I have ME/CFS, chronic lyme, hashimoto’s, celiac disease, leaky gut syndrome. In 2009 I came down with a severe flu like illness. I have never been the same. In the few months preceding that illness I developed cystic acne all over my face, severe exhaustion, etc. I had not had acne in my previous 49 years of life.” In my case no acne in my previous 30 years of my life. no hashimoto’s. But Bartonella and Borelia lyme.

Valerie

Hi Cort and everyone,
I too found this a surprising outcome. I guess I would still fall under typical or classical if I got it with a flu-like onset one year after childbirth, and then developed celiac disease, right?

Cort Johnson

Prashanti

Cort,
I know this isn’t the correct thread to respond to you, however, I can’t find the right one….Some time ago you posted something about a personal trial you were doing I think with some kind of stimulator. I replied that I had access to an alpha-stim machine and was trying that. You wanted follow up from me.
It was off and on giving me more energy…now there seems to be a break through. I can get through most days without crashing or even needing a nap. It’s been amazing! I have been using it most of the time for aroun 7 months. Well worth the money.
However, I’m not totally certain the recent break through has been due totally to the alpha-stim as I have also started taking homeopathic drops for Epstein Barr (which I have) and a viral immune formula. I’m keeping those up and asking the Dr at Stanford to retest for EBV to see if there has been progress. She had previously prescribed an antiviral drug that my digestive system couldn’t handle.

Cort Johnson

Natalie S

Hi, I was wondering about the disease duration subgroups. Long/short refers to how long a patient had been ill at the time of sample collection. Was any follow up done to see if patients had recovered? While there are clear differences in immune signatures in early vs later disease, this paper and the previous work by Hornig/Lipkin can’t be used to predict whether someone will be ill for a shorter or longer time, right?

A,

I think I may be in the atypical subset. I got ME/CFS after an infection that I caught during foreign travel. However, I was already back home and seemingly getting over the infection, when I got ill. Years later, I got diagnosed with Psoriasis. It is an autoimmune disease, but not one like M.S.. My family does have other ME/CFS cases, as well as Lymphoma.Would be interested to know if other familial studies are upcoming, since up above, Issie said Bateman’s study is closed. How do we get in touch with the Lights?

I just wish Simmaron study wasn’t published in a Psychiatry journal, as my doctors already seem to think this disease is psychological.

Thank you, Cort! 🙂

A.

I think I’m in the atypical group, since my disease started after an infection I caught during foreign travel and I have an autoimmune disease. I remember that Peterson earlier said that atypical patients don’t fare as well with current treatments – certainly my experience. Hope future research leads to better treatment for us all!

Susan

My CFS/ME onset was after a round of vaccines that I was getting going into the Peace Corps (foreign travel)…how many of these subsets got vaccines before foreign travel. “have been exposed to unusual pathogens during foreign travel”

Sarah Stanton

I think I must be in the atypical onset category too. Fell sick after visiting China in 2009, came down with gastro from the water while I was there and swine flu after the flight back home, either of which could’ve triggered it. Rather than being floored instantly I had a very slow deterioration over a number of years, starting out with extreme hypersomnia, fatigue and brain fog but not getting any pain for several years. I struggled but managed to hold down a mostly functioning life in those years. Eight years on and I have dxes of ME, fibro, IBS, interstitial cystitis, as well as a bunch of others I had before getting sick. It’s hard enough to know you have ME/CFS without having to deal with knowing you have a worse outlook and a higher chance of a whole bunch of terrible bonus illnesses on top of it. =/

Those of you who know me or have followed my testimony to CFSCC and CFSAC, know that I’ve testified for almost 2 decades about having biomarkers – that they either would work for all of us, or that I was part of a subset clearly defined by biomarkers. As the years have gone by we’ve added more to the list. This is one way I’ve marked improvement on Ampligen – the biomarkers go away and my viruses go dormant.

I was in this study, and I’m abnormal. No surprise to me. At the time (2009, when I had been off Ampligen almost 18 months), I also tested positive for HHV-6 and CMV in my spinal fluid. It’s unfortunate that the method of saving the spinal fluid precluded being able to test for viruses, but that’s okay – we have other records. And I don’t think Lipkin intends to give up on that.

Maybe NIH and CDC will quit saying “that’s nonsense” or “you people test positive for viruses you don’t have” or “those aren’t real biomarkers – they’re normal errors” or other dismissive responses if I go back and testify again.

But whether or not you fit in THESE two sets, and whether or not they are the same disease, two subsets, shifting to biomarkers instead of subjective questionnaires would be a blessing for all of us.

And I also think it’s interesting that I am so responsive to Ampligen – as are a number of my friends who test positive for the same things.

Cort Johnson

dejurgen

My ME came slowly increasing over the years after I got mono as a young adult. The case of mono in itself was atypical: I had completely no fever and no swollen glants. In fact, my body was freezing cold.

Maybe this is a case of insufficient immune response at the time of infection? At the moment I however have no nasty additional disease yet so I’ll hope I’m in the safe subgroup. Still, checking if the atypical cases had fever at time of onset may be an easy task to do.

Flo

Carolyn Richards

I originally had EBV in Feb. of 1989. Ran a low grade fever & doctor treated me with antibiotics for a period of time & kept me coming back & said I had CEBV. There were evidently several people in our subdivision that had acquired EBV but didn’t know them. (I was on city water for the first time in my life) This was near the Toledo area. Was better for a while & then got diagnosed with Lyme after move to Florida. Treated with 6 weeks IV Rocephin plus other oral antibiotics. Got better for a while. Notice I keep saying better (not well). Then went to University of Miami & Klimas diagnosed me with Chronic Fatigue Immune Dysfunction Syndrome but sent me on to Dr. Sheramata who was their MS specialist in Miami. Sheramata diagnosed me with MS. (stating there were many kinds of MS but I had something in addition to CFIDS) Sheramata (according to Osler’s Web) was sent to the Florida keys to investigate a MS cluster. By this time I was not excited about the medical community & decided to not take any treatment for the MS. Had started seeing an Infectious Disease doctor locally & from a routine chest x ray they thought mild fibrosis. I had sent blood tests to Garth Nicholson’s group who did PCR on mycoplasma & was diagnosed with M. Pneumonia. ID doctor started me on doxycycline first & was amazed how my cognition had improved. He said I had difficulty completing a sentence as I would lose my train of thought. I was given other various antibiotics at the time & got better for awhile (again). Surprised Pulmonologist as they were scheduling a scan & biopsy based on my chest x ray. Eventually went to a Rheumatologist & he said I had RA from tests. He wanted me to take Methotrexate & Plaquenil. I suggested one at a time as I had difficulty with meds. Took Plaquenil for about 3 or 4 weeks & broke out in a rash (discontinued). I had had previous food testing via blood (not sure how reliable as much controversy on that also. I had almost 50% sensitives on the food testing. Have had a shortness of breath since the beginning but attributed that to smoking but quit around 97.
Diagnosed with lung cancer in 2012 (one tumor in upper) they removed lobe of lung. Had a stroke from surgery (I remember waking up & was in horrific pain & all went blank). Stopped seeing all doctors except primary at this time. Started getting extremely worse & went to cardiologist & rheumatologist (he didn’t find the same results as before) so guess I don’t have RA. Then in 2017 right after seeing the Rheumatologist I acquired enlarged nodes mid neck & primary sent of testing & then on to an Oncologist who diagnosed me with Mantle Cell Lymphoma. I understand that MCL was one of the reasons Mikovitz became interested in ME/CFS. Had Bendamustine Rituxan & am now (stable). I guess there is no doubt I would fall into the atypical group. I did forget to mention that after my CEBV in Feb. I lost my oldest son that October in 1989 that I am sure attributed to my downward spiral. I read some research a very long time ago where a test was done with rats. They injected the rats with a dye & then stressed them by making them swim for long distances. The rats that were stressed had dye seepage into their brains. Thought I should tell my story & share my thoughts as I have been reading research since around 1997. Just noticed that most of the reply’s were from 2017

CWB

Dear Carolyn–Thank you for sharing your story. Yes, you seem to fit into the atypical group. I’m sorry–for all of the the road you’ve had to take and for the loss of your son. We don’t really “get over” losses like that, we just carry them differently over time. The same is true for chronic illness. I have to believe that forums like this, where stories and replies are archived for easy reference–as opposed to social media threads which are mostly lost–will get the attention of researchers. I hope there will be breakthroughs and treatments for you, for us all.

Grace Ward

Sudden onset after a viral infection in April 1998. Tested for EBV but was negative for active ebv, tests indicated i had ebv in the past. I’ve never tested active since onset. Went through a ton of hearing, high titers for Mycoplasma Pneumonia but within normal range. Biopsy of lymph node showed active macrophages, t cell something and whatever it was the doctor told me my body was actively fighting an infection. Most all of my doctors have only run tests after i brought in research ideas.

Recently tested positive to the FMA testing. The only cancer diagnosed was precancer. Hopefully because i get regular checkups. I do have serious outbreaks of herpes virus that’s been so since this last year that i have asked my dr for refills of antiviral for herpes quite more often than the past 20 years. I had one psychologist who had some experience with people with EDS but i’ve never been tested for it.

Hypermobility has been a reason for chronic wrist, knee, ankle, and shoulder injuries/ stains/ tears/ surgeries.. It took me years to accept the diagnosis of CfIDS and FMS. Have hypersomnia most of the time mixed with insomnia when the weather is changing at night. Low blood pressure for years until lately when it started causing to higher than normal.

Brain fog. Easily forget and hard to remember words or directions. I feel like an idiot, I look high all the time, my skin is quickly losing elasticity after menopause, have severe mood swings, vertigo or is ot my brain spinning. As far as the base of my brain, even though no one’s treated the spinal fluid, it is very backed up there. Slight chiari malformation, swolen glands, yet, I’m slender so my physician believes this is normal, which i argue is not, because they swell in my groin, neck, and behind my right ear and are tender.

All I know is that one day in 1998 i got a flu like illness. I’ve had short spells that i could manage 4 good days. 3 bad to months of exhaustion with a day here and there that i could manage living like around it. Never to be back to my old self and now i find there’s no darn funding??? I’m not what you’d call atypical as far as what you’ve explained. But this is still debilitating most of the time.

I can’t figure out for the life of me, how i have actually had a day show up ot of nowhere that i feel like my old self completely just for it to go away and have no rhyme or reason for that to happen. In 20 years I could say that 4 times a year this has happened. Last year it was new year’s eve and day, then one day during the summer, and 1 day in the fall. I will push myself to get through urgent situations and then crash/burn and can’t push just to get through a normal day.

Why is that? How is that even possible when I’m sick almost all the time?

CWB

Grace, our paths are so similar. This no-rhyme-or-reason good days are baffling, as are the awful ones after so much rest, caution, and discipline to live within one’s energy envelope. All I can say is that I hope you have a couple of those happy surprises over the upcoming holidays. Thankfully the science seems to be closing in on more answers, better answers, maybe real help.